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Ganesh Acharya, Juha Räsänen, Kaarin Mäkikallio, Tiina Erkinaro, Tomi
Kavasmaa, Mervi Haapsamo, Luc Mertens and James C. Huhta
Am J Physiol Heart Circ Physiol 294:498-504, 2008. First published Nov 16, 2007;
doi:10.1152/ajpheart.00492.2007
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Am J Physiol Heart Circ Physiol 294: H498–H504, 2008.
First published November 16, 2007; doi:10.1152/ajpheart.00492.2007.
Metabolic acidosis decreases fetal myocardial isovolumic velocities
in a chronic sheep model of increased placental vascular resistance
Ganesh Acharya,1,2 Juha Räsänen,3 Kaarin Mäkikallio,3 Tiina Erkinaro,4 Tomi Kavasmaa,4
Mervi Haapsamo,3 Luc Mertens,5 and James C. Huhta1
1
Department of Pediatrics, University of South Florida College of Medicine and All Children’s Hospital, Children’s Research
Institute, St. Petersburg, Florida; 2Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tromsø,
and University Hospital of Northern Norway, Tromsø, Norway; Departments of 3Obstetrics and Gynecology
and 4Anesthesiology, University Hospital of Oulu, Oulu, Finland; and 5Department of Pediatric Cardiology, University
Hospital Leuven, Leuven, Belgium
Submitted 24 April 2007; accepted in final form 12 November 2007
cardiac function; fetal echocardiography; tissue Doppler
IN RESPONSE TO HYPOXEMIA, fetuses generally redistribute more
blood toward the myocardium, brain, and adrenal glands at the
expense of the lower body and viscera (3, 22). The fetal heart
is known to have a remarkable ability to withstand hypoxia
(10, 30), but progressive hypoxia and acidosis may decrease
blood supply to the heart (6) and alter myocardial energy
metabolism (18, 40). However, despite reduced myocardial
contractility, global cardiac function is preserved during mod-
Address for reprint requests and other correspondence: G. Acharya, Dept. of
Pediatrics, Univ. of South Florida College of Medicine and All Children’s
Hospital, Children’s Research Institute, 801 6th St. South, Box 9365, St.
Petersburg, FL 33701 (e-mail: [email protected]).
H498
erate acidemia (26). Echocardiography has been applied to
assess fetal cardiac function noninvasively in a variety of
clinical conditions, such as intrauterine growth restriction (29),
hydrops (17), congenital heart disease (38), and twin-twin
transfusion syndrome (36). Recently, tissue Doppler imaging
(TDI) of myocardial motion has been introduced in clinical
practice as a promising new technique in the assessment of
fetal heart function (2, 8, 11, 15, 32, 34).
In human pregnancies, placental insufficiency with increased placental vascular resistance (Rua) can lead to fetal
metabolic acidosis and death. Our experiments in a chronic
sheep model of increased Rua were designed to test the hypothesis that acute metabolic acidosis decreases fetal myocardial
motion. We asked the following questions. 1) How does the
fetal myocardium tolerate metabolic acidosis? 2) Does acute
metabolic acidosis with increased Rua affect longitudinal myocardial wall motion and TDI parameters describing cardiac
function?
METHODS
Measurements were made on 11 Finnish pregnant sheep (gestational age 123–127 days, full-term 145 days) that were part of a
research protocol investigating fetomaternal cardiovascular function
in a model of increased Rua. All experiments were performed in
accordance with the guidelines of the European Convention for the
Protection of Vertebrate Animals Used for Experimental and Other
Scientific Purposes (1986) and in compliance with European Union
Directive 86/609/EEC (1997). The research protocol was approved by
the Animal Care and Use Committee of the University of Oulu.
Surgical procedure and instrumentation. After they were fasted
overnight, the sheep were premedicated intramuscularly with ketamine (2 mg/kg) and midazolam (0.2 mg/kg). Venous access was
obtained by cannulation of an auricular vein. General anesthesia was
induced with propofol (4 –7 mg/kg iv). Anesthesia was maintained
with isoflurane (1–2.5%) in an oxygen-air mixture delivered via an
endotracheal tube; intravenous boluses of fentanyl were administered
as required. A catheter was inserted into the ewe’s external left jugular
vein to serve as a permanent intravenous line, and an auricular artery
was cannulated for blood pressure (BP) and heart rate monitoring.
Mechanical ventilation was maintained throughout the surgical
procedure.
A midline laparotomy was performed, and a 6-mm transit-time
ultrasonic flow probe (Transonic Systems, Ithaca, NY) was placed
around the uterine artery supplying the pregnant uterine horn. ThereThe costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
0363-6135/08 $8.00 Copyright © 2008 the American Physiological Society
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Acharya G, Räsänen J, Mäkikallio K, Erkinaro T, Kavasmaa
T, Haapsamo M, Mertens L, Huhta JC. Metabolic acidosis decreases fetal myocardial isovolumic velocities in a chronic sheep
model of increased placental vascular resistance. Am J Physiol Heart
Circ Physiol 294: H498–H504, 2008. First published November 16,
2007; doi:10.1152/ajpheart.00492.2007.—We hypothesized that acute
fetal metabolic acidosis decreases fetal myocardial motion in a
chronic sheep model of increased placental vascular resistance (Rua).
Eleven ewes and fetuses were instrumented at 118 –122 days of
gestation. After 5 days of recovery and 24 h of placental embolization
to increase Rua, longitudinal myocardial velocities of the right and left
ventricles and interventricular septum (IVS) were assessed at the level
of the atrioventricular valve annuli via tissue Doppler imaging (TDI).
Ventricular inflow (E and A waves) and outflow velocities were
obtained, and cardiac outputs were calculated. All measurements were
performed at baseline and during fetal acidosis caused by epidural
anesthesia-induced maternal hypotension, which decreased uterine
artery volume blood flow, fetal oxygenation, arterial pH, and base
excess and increased lactate. Compared with baseline, the peak
isovolumic myocardial contraction and relaxation velocities of the
ventricles and IVS, early relaxation velocity (E⬘) of the ventricles, and
systolic velocity of the IVS decreased during metabolic acidosis. The
proportion of isovolumic contraction time of the cardiac cycle increased but the isovolumic relaxation and ejection time proportions
and the TDI Tei index did not change. The E-to-E⬘ ratio for both
ventricles was higher during metabolic acidosis than at baseline.
During metabolic acidosis, right and left ventricular cardiac outputs
remained unchanged compared with baseline. In sheep fetuses with
increased Rua and acute metabolic acidosis, global cardiac function
was preserved. However, acute metabolic acidosis impaired myocardial contractility during the isovolumic phase and relaxation during
the isovolumic and early filling phases of the cardiac cycle.
H499
MYOCARDIAL VELOCITIES IN FETAL ACIDOSIS
after, the fetal lower body was exposed through a small incision on the
anterior uterine wall. Polyurethane catheters (18 gauge) were inserted
into the fetal descending aorta and inferior vena cava via the femoral
artery and vein, respectively. A small transverse incision was made on
the fetal abdomen just below the umbilical cord insertion, and the
umbilical arteries were exposed. A 4-mm transit-time ultrasonic flow
probe (Transonic Systems) was placed around the umbilical arteries
and secured to the fetal abdomen. Then the fetus was returned to the
uterine cavity, the lost amniotic fluid was replaced with warm 0.9%
NaCl, and the hysterotomy and laparotomy incisions were closed. The
catheters and flow probes were tunneled subcutaneously and exteriorized through a small skin incision and secured to the ewe’s flank.
For postoperative analgesia, a fentanyl patch was attached to the
ewe’s tail, and intramuscular fentanyl (2 ␮g/kg) was given in the first
48 h and buprenorphine (0.01 mg/kg) thereafter. The ewes were
intravenously infused with 1 liter of Ringer lactate solution and 1 g of
ampicillin daily and the fetuses with 1 ⫻ 106 U of benzyl penicillin
daily.
In human pregnancies complicated by placental insufficiency and
increased placental vascular impedance, the number of small tertiary
villi arterioles is significantly reduced (12). To simulate this pathophysiological condition, we chose to embolize the placenta on postoperative day 4 with 45- to 150-␮m microspheres (Contour Emboli,
Target Therapeutics, Fremont, CA). A dry volume of 0.25 ml of
microspheres was suspended in 0.5 ml of 20% albumin and diluted
with 10 ml of 0.9% NaCl. This solution was injected into the fetal
descending aorta via the femoral artery catheter in 1-ml increments
every 15 min until fetal arterial oxygen saturation decreased by 30%
from preembolization values.
Table 1. Results of arterial blood gas analysis and acid-base status of sheep fetuses before placental embolization, at
baseline, and during metabolic acidosis
Preembolization
Baseline
Acidosis
pH
Arterial PO2, mmHg
Arterial PCO2, mmHg
BE, mmol/l
Lactate, mmol/l
7.32⫾0.04
7.27⫾0.07
7.04⫾0.13*
23.5⫾3.5
19.6⫾4.3
14.4⫾4.8‡
49.2⫾5.0
55.7⫾6.9
72.1⫾16†
⫺2.0⫾2.7
⫺1.0⫾2.86
⫺11.0⫾4.14*
1.6⫾0.6
3.1⫾1.6
9.8⫾2.1*
Values are means ⫾ SD (n ⫽ 11). BE, base excess. *P ⬍ 0.0001; †P ⫽ 0.002; ‡P ⫽ 0.004 vs. baseline.
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Fig. 1. Longitudinal myocardial velocities obtained at the level of mitral valve
(mv an) annulus from a sheep fetus 24 h after placental embolization (baseline). Note typical waveforms and cardiac cycle time intervals. IVCV, isovolumic contraction velocity; IVCT, isovolumic contraction time; IVRV,
isovolumic relaxation velocity; IVRT isovolumic relaxation time; ET, ejection
time; S⬘, systolic contraction velocity; E⬘, early myocardial relaxation velocity;
A⬘, myocardial relaxation velocity during the atrial contraction phase of
diastole.
Data acquisition. Data were acquired from anesthetized animals on
postoperative day 5, ⬃24 h after placental embolization. General
anesthesia was induced with propofol (4 –7 mg/kg iv) and maintained
with isoflurane (1–1.5%) in a 40% oxygen-air mixture delivered via
an endotracheal tube. Rocuronium (20 mg) was used for muscle
relaxation to facilitate mechanical ventilation. Tidal volume was
adjusted to 8 –10 ml/kg and respiratory rate to 18 min⫺1.
A 16-gauge polyurethane catheter was inserted into the descending
aorta of the sheep via a femoral artery for monitoring aortic BP. In
addition, a 19-gauge epidural catheter was placed into the epidural
space just above the lumbosacral junction. Ringer lactate solution was
infused at a fixed rate of 200 ml/h through the external jugular vein
access. The sheep was positioned supine with a right lateral tilt. The
animals were allowed to stabilize for 30 min before the baseline
measurements were made.
Fetal metabolic acidosis was induced by reduction of uterine artery
volume blood flow (Quta). Bupivacaine (0.5%) was administered
through the epidural catheter to a total dose of 0.3 ml/kg maternal
body wt 2 min after an initial test dose of 5 ml, and hypotension was
allowed to develop to a ⱖ20% decrease in maternal systolic BP.
The criteria for fetal metabolic acidosis were as follows: arterial
pH ⬍7.20, base excess less than ⫺6 mmol/l, and lactate ⬎6 mmol/l.
The aortic BP and central venous pressure (CVP) of the ewe and
the fetus were continuously monitored using disposable pressure
transducers (model DT-XX, Ohmeda, Hatfield, UK). Pressure transducers were first zeroed against the atmospheric pressure and then
calibrated using a 150-cm intravenous line filled with water. Pressure
of 150 cmH2O is equivalent to 110 mmHg. Mean arterial pressure
(MAP) was calculated as follows: MAP ⫽ diastolic BP ⫹ 1/3(systolic
BP ⫺ diastolic BP). Quta and umbilical artery volume blood flow
(Qua) were measured directly with perivascular transit-time ultrasonic
flow probes (model T206, Transonic Systems). Rua was calculated as
follows: Rua ⫽ fetal MAP/Qua. All these variables were recorded
continuously at a sampling rate of 100 Hz using a polygraph (model
UIM100A, Biopac Systems, Santa Barbara, CA) and computerized
data acquisition software (Acqknowledge version 3.5.7 for Windows,
Biopac Systems).
Ultrasonography was performed using the Vivid 7 Dimension
ultrasound system (GE Vingmed Ultrasound, Horten, Norway) with a
10-MHz phased-array transducer. Ventricular inflow and outflow
blood velocity waveforms were obtained using pulsed Doppler
ultrasonography, with the insonation angle maintained at ⬍15°.
Time-velocity integrals of pulmonary and aortic valve blood velocity
waveforms were measured by planimetry of the area underneath the
Doppler spectrum. Pulmonary and aortic valve diameters were obtained to calculate their cross-sectional areas (CSA). Right and left
ventricular cardiac outputs were calculated (Q ⫽ time-velocity integral ⫻ CSA ⫻ fetal heart rate) (37). The longitudinal velocities of the
right ventricle (RV), left ventricle (LV), and interventricular septum
(IVS) during the cardiac cycle were assessed using pulsed-wave TDI,
with the sample volume (1–1.5 mm) placed at the level of the
atrioventricular valve annuli and aligned as parallel as possible to the
myocardial wall (⬍15° angle of insonation). Myocardial velocities
were recorded during three to six cardiac cycles at a sweep speed of
100 mm/s. All measurements were performed at baseline and during
fetal metabolic acidosis by a single investigator.
H500
MYOCARDIAL VELOCITIES IN FETAL ACIDOSIS
using the Pearson correlation coefficient. Statistical significance
was set at P ⱕ 0.05.
RESULTS
Tissue Doppler traces were analyzed offline using EchoPac PC
software (version 6.0.0, GE Medical Systems). Maximal myocardial
velocities were measured during isovolumic relaxation (IVRV), early
ventricular filling (E⬘), atrial contraction (A⬘), isovolumic contraction
(IVCV), and ventricular systole (S⬘). The slopes of isovolumic myocardial acceleration and deceleration were calculated by dividing the
peak IVCV and IVRV by the time intervals from the onset to the peak
of these velocity waveforms, respectively. Ventricular and septal
isovolumic contraction time (IVCT), isovolumic relaxation time
(IVRT), ejection time (ET), and the total duration of the cardiac cycle
were measured using pulsed-wave tissue Doppler traces (Fig. 1). The
TDI Tei index (41) was calculated by dividing the sum of IVCT and
IVRT by ET.
Fetal arterial blood samples were analyzed for acid-base status
(corrected for 39°C) using an i-Stat 1 analyzer (i-Stat, East Windsor,
NJ). At the end of the experiment, the animals were euthanized with
a lethal dose of pentobarbital sodium.
Data were analyzed using Statistical Software for Social Sciences
for Windows version 14.0 (SPSS, Chicago, IL). For continuous
parametric variables, the paired t-test was used to examine differences between baseline and acidosis. Correlations were tested
Table 2. TDI parameters of fetal left ventricle at the level of the mitral valve annulus
Baseline
Acidosis
P
S⬘, cm/s
E⬘, cm/s
A⬘, cm/s
IVCV,
cm/s
IVRV,
cm/s
Accel, cm/s2
Decel,
cm/s2
E/E⬘
IVRT, %
IVCT, %
ET, %
Tei Index
8.7⫾2.0
7.5⫾1.1
0.096
7.7⫾1.3
6.2⫾1.3
0.022
12.8⫾3.0
11.7⫾2.4
0.364
6.1⫾2.3
4.3⫾1.8
0.006
4.0⫾0.9
2.6⫾0.7
⬍0.0001
628⫾231
305⫾97
⬍0.0001
357⫾88
205⫾61
⬍0.0001
5.21⫾1.3
7.74⫾1.3
0.007
14.0⫾6.8
13.5⫾3.8
0.827
8.1⫾3.1
10.7⫾3.8
0.047
36⫾6.9
38⫾4.3
0.450
0.61⫾0.16
0.65⫾0.16
0.445
Values are means ⫾ SD. TDI, tissue Doppler imaging; S⬘, systolic contraction velocity; E⬘, early diastolic relaxation velocity; A⬘, velocity during atrial
contraction; IVCV, isovolumic contraction velocity; E, ventricular inflow velocity during early filling; IVRV, isovolumic relaxation velocity; Accel, isovolumic
myocardial acceleration; Decel, isovolumic myocardial deceleration; IVRT, isovolumic relaxation time; IVCT, isovolumic contraction time; ET, ejection time.
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Fig. 2. Longitudinal myocardial velocities obtained at the level of the mitral
valve annulus from sheep fetuses during tachycardia (A) and bradycardia (B).
Note merged E⬘ and A⬘ waves (i.e., monophasic relaxation) in A and widely
spaced E⬘ and A⬘ waves in B. Trace is oriented from an apical view, such that
systolic deflections (S⬘) are above the zero line and toward the transducer.
The mean weight of the ewes (n ⫽ 11) was 56 (range
49 – 61) kg. The mean gestational age on the day of the
experiment was 125 (range 123–127) days, and the mean fetal
weight was 2,190 (range 1,220 –2,675) g. During hypotension,
maternal MAP (87 ⫾ 8 vs. 65 ⫾ 14 mmHg, P ⬍ 0.0001) and
Quta (472 ⫾ 223 vs. 223 ⫾ 141 ml/min, P ⫽ 0.004) were
reduced compared with baseline. Qua (89 ⫾ 32 vs. 58 ⫾ 39
ml 䡠kg⫺1 䡠min⫺1, P ⫽ 0.01) decreased, while the fetal heart rate
(151 ⫾ 35 vs. 158 ⫾ 25 beats/min, P ⫽ 0.533), MAP (50 ⫾
8 vs. 47 ⫾ 7 mmHg, P ⫽ 0.245), and CVP (14 ⫾ 6 vs. 15 ⫾
7 mmHg, P ⫽ 0.339) remained unchanged. During maternal
hypotension, Rua (0.291 ⫾ 0.102 vs. 0.402 ⫾ 0.114
mmHg䡠ml⫺1 䡠min⫺1, P ⫽ 0.007) was increased compared with
baseline. The results of fetal arterial blood gas analysis and
acid-base status are presented in Table 1.
It was possible to obtain good-quality images of pulsedwave tissue Doppler recordings of the longitudinal myocardial
velocities of the RV, LV, and IVS in all cases by transabdominal echocardiography. Typically, the TDI waveform recordings showed IVCV, S⬘, IVRV, E⬘, and A⬘ waves (Fig. 1).
However, in some fetuses, we observed monophasic myocardial relaxation velocity (fused E⬘ and A⬘ waves) during tachycardia (Fig. 2A) and a prolonged period of myocardial quiescence between the early relaxation phase and the atrial contraction phase of diastole (widely separated E⬘ and A⬘ waves)
during bradycardia (Fig. 2B).
Fetal myocardial TDI parameters obtained from the
LV, RV, and IVS at the level of the atrioventricular valve
annuli during baseline and metabolic acidosis are shown in
Tables 2, Tables 3, and Tables 4, respectively. The TDI
parameters were not significantly different between the two
ventricles. Compared with baseline, the peak IVCV, IVRV,
and the slopes of isovolumic myocardial acceleration and
deceleration of the ventricles and IVS decreased significantly
during fetal acidosis (Fig. 3). The peak early relaxation (E⬘
wave) velocity of both ventricles and the peak systolic (S⬘)
velocity of the IVS also decreased significantly during acidosis. During fetal acidosis, the proportion of IVCT of the cardiac
cycle (IVCT%) increased but the Tei index did not change
significantly from the baseline value for both ventricles as well
as the IVS. The E-to-E⬘ ratio (E/E⬘) for both ventricles was
significantly higher during acidosis than at baseline.
The peak IVCV, IVRV, and the slopes of isovolumic myocardial acceleration and deceleration of the LV, RV, and IVS
correlated significantly with fetal pH, except the RV peak
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MYOCARDIAL VELOCITIES IN FETAL ACIDOSIS
Table 3. TDI parameters of fetal right ventricle at the level of the tricuspid valve annulus
Baseline
Acidosis
P
S⬘, cm/s
E⬘, cm/s
A⬘, cm/s
IVCV,
cm/s
IVRV,
cm/s
Accel, cm/s2
Decel,
cm/s2
E/E⬘
IVRT, %
IVCT, %
ET, %
Tei Index
9.5⫾2.0
8.5⫾2.3
0.173
7.1⫾1.0
5.7⫾1.4
0.008
11.2⫾3.0
11.5⫾2.4
0.728
5.5⫾1.7
4.1⫾1.5
0.013
4.0⫾0.8
2.9⫾0.7
0.003
596⫾170
290⫾106
0.001
335⫾74
206⫾61
⬍0.0001
5.48⫾1.09
7.07⫾1.41
0.026
14.2⫾5.7
15.9⫾2.6
0.427
7.6⫾3.1
10.3⫾3.6
0.050
38⫾6.6
38⫾6.0
0.967
0.57⫾0.15
0.70⫾0.16
0.138
Values are means ⫾ SD.
DISCUSSION
With our experimental animal model, we have tried to
replicate the pathophysiological situation in human placental
insufficiency, in which placental dysfunction can lead to fetal
acidosis and death. Fetal hypoxia and acidosis can be induced
by maternal hypooxygenation (35) or a reduction in Qua (19)
and Quta (23). Our experiments in a sheep model of increased
Rua were designed to study fetal myocardial function during
acute metabolic acidosis induced by a reduction of Quta. We
used TDI-derived longitudinal myocardial velocities and cardiac cycle time intervals to infer information on fetal cardiac
function.
Myocardial contractility was assessed by the slope of isovolumic myocardial acceleration, which is independent of
cardiac loading conditions (42, 43). Other indexes describing
cardiac systolic function included peak IVCV, IVCT%, and
peak S⬘ wave velocity. Preejection indexes are less influenced
by afterload than ejection phase indexes (27). The slope of
isovolumic myocardial deceleration, peak IVRV, IVRT%, and
peak E⬘ and A⬘ wave velocities were used to assess myocardial
relaxation and diastolic properties. IVRT and E⬘ wave velocity
are known to be affected by cardiac loading conditions (21).
Global cardiac function was evaluated by TDI Tei index and
ventricular cardiac outputs. In the present study, mean Rua was
⬃1.4-fold higher during acidosis than at baseline. This can lead
to an increase in cardiac afterload. However, when we investigated the relationships between ⌬Rua and TDI parameters,
only septal ICT% and Tei index demonstrated significant
correlations with the increase in Rua.
We were able to detect a decrease in the slope of isovolumic
myocardial acceleration and peak IVCV and an increase in
IVCT% during fetal acidosis. These findings suggest that
metabolic acidosis decreases myocardial contractility. The
slope of isovolumic myocardial acceleration and the other
preejection indexes reflect the ability of the myocardium to
generate pressure sufficient to overcome systemic diastolic
pressure. These have been validated as noninvasive indexes of
myocardial contractility in animal experiments (42, 45). A rise
in placental vascular resistance can increase cardiac afterload,
which may influence preejection and ejection indexes. On the
other hand, fetal MAP did not change significantly during
metabolic acidosis. In addition, experimental studies have
shown that RV and LV slopes of isovolumic myocardial
acceleration are not affected by loading conditions. In fact, it
appears that ventricular peak S⬘ wave velocity, which did not
change significantly during metabolic acidosis in the present
study, is the most sensitive index to increased afterload (43).
Our observation of reduced myocardial contractility during
fetal acidosis is consistent with the results of in vitro experiments demonstrating decreased isometric tension development
in isolated fetal myocardial fibers within 10 min of profound
hypoxia (40) and reduced myocardial contractility when LV
function was assessed in vivo in sheep fetuses by end-systolic
elastance using a conductance catheter during acidosis induced
by placental embolization (26).
We observed that the waveform of myocardial lengthening
velocity during isovolumic relaxation (IVRV) could be consistently recorded by pulsed TDI (Fig. 1). This velocity has
not been previously described in the literature. During fetal
acidosis, we found that the peak IVRV and the slope of
isovolumic myocardial deceleration are reduced. Additionally, a reduction in E⬘ wave velocity (an index of active
ventricular relaxation) was noted, but no significant change
in the A⬘ wave velocity was observed. These findings suggest
that metabolic acidosis can adversely affect the calcium- and
energy-dependent active myocardial relaxation during the isovolumic phase and the early phase of diastole, but the ventricular expansion during atrial contraction is not significantly
affected; i.e., the atrial contractility is preserved. This is consistent with the finding that, in coronary artery disease, A⬘
wave velocity is significantly higher among patients with
preserved LV ejection fraction (⬎50%) than in those with
impaired ejection fraction (44). A change in the cardiac after-
Table 4. TDI parameters at the septal annulus
Baseline
Acidosis
P
S⬘, cm/s
E⬘, cm/s
A⬘, cm/s
IVCV, cm/s
IVRV, cm/s
Accel, cm/s2
Decel, cm/s2
IVRT, %
IVCT, %
ET, %
Tei Index
8.1⫾2.4
6.3⫾1.0
0.031
5.2⫾1.0
4.2⫾1.9
0.120
8.5⫾2.4
8.4⫾2.2
0.714
4.8⫾1.4
3.5⫾1.3
0.003
4.0⫾1.1
2.8⫾0.6
0.003
523⫾170
284⫾88
0.002
372⫾128
259⫾71
0.019
12.1⫾4.8
11.9⫾2.4
0.856
7.4⫾2.6
9.9⫾3.8
0.033
37⫾6.5
38⫾4.8
0.401
0.54⫾0.13
0.57⫾0.11
0.458
Values are means ⫾ SD.
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IVRV. The LV and IVS Tei indexes correlated significantly
with fetal pH, but the RV Tei index did not (Table 5). When we
examined the relationships between the increase in Rua from
baseline to the acidosis phase (⌬Rua) and TDI parameters, only
⌬IVS IVCT% (r ⫽ 0.65, P ⬍ 0.031) and ⌬IVS Tei index
(r ⫽ 0.64, P ⬍ 0.034) showed significant correlations.
The fetal LV (412 ⫾ 178 vs. 449 ⫾ 199 ml/min, P ⫽ 0.511),
RV (584 ⫾ 283 vs. 588 ⫾ 300 ml/min, P ⫽ 0.971), and LV ⫹
RV (996 ⫾ 454 vs. 1,037 ⫾ 449 ml/min, P ⫽ 0.791) cardiac
outputs during acidosis were comparable with baseline values.
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MYOCARDIAL VELOCITIES IN FETAL ACIDOSIS
load can affect indexes describing myocardial relaxation and
diastolic properties (25). However, IVRT%, which is known to
be affected by changes in loading conditions, remained stable
during metabolic acidosis, suggesting that our findings merely
reflected the effects of metabolic acidosis. Glucose and lactate
account for the majority of myocardial oxygen consumption in
sheep fetuses (5), and significant metabolic acidosis leads to
depletion of myocardial glycogen and ATP stores, which is
associated with impaired repolarization, as evidenced by
T wave changes in the fetal electrocardiogram (18). Therefore,
inasmuch as disturbances in diastole often precede and may
occur independent of changes in global systolic performance,
diastolic function assessment can be useful in monitoring
fetuses at risk for cardiac dysfunction.
The relatively high TDI Tei indexes in our fetuses at baseline may be explained by increased Rua and higher afterload
following placental embolization. The TDI Tei index is
shown to correlate with the Tei index obtained by pulsedwave Doppler and M-mode echocardiography (9) but is
affected by loading conditions (7). A previous study in human
fetuses with heart failure (2) suggested that the TDI Tei index
maybe a sensitive parameter in the assessment of RV function.
We observed no significant changes in fetal ventricular
cardiac outputs or ventricular TDI Tei indexes during the
experiments. In the absence of altered BPs, abnormal relaxation causes longer IVRT and an increase in Tei index values.
However, inasmuch as the fetal aortic pressure and CVP during
acidosis were not significantly different from baseline values in
our study, it is unlikely that the elevated atrial pressure has
masked a detectable rise in the Tei index during acidosis. This
suggests that the global cardiac function is relatively well
preserved during acute metabolic acidosis, consistent with
AJP-Heart Circ Physiol • VOL
Table 5. Correlations between TDI parameters and fetal
pH values
Pearson’s r
P
Left ventricle
IVCV
Accel
IVRV
Decel
Tei index
E/E⬘
0.54
0.68
0.58
0.61
⫺0.62
⫺0.71
0.01
⬍0.0001
0.005
0.003
0.002
0.005
Right ventricle
IVCV
Accel
IVRV
Decel
Tei index
E/E⬘
0.54
0.69
0.39
0.43
⫺0.25
⫺0.49
0.01
⬍0.0001
0.074
0.044
0.271
0.065
Interventricular septum
IVCV
Accel
IVRV
Decel
Tei index
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0.62
0.59
0.44
0.55
⫺0.67
0.002
0.004
0.04
0.008
0.001
Downloaded from ajpheart.physiology.org on August 3, 2008
Fig. 3. Myocardial velocities obtained at the septal annulus of a sheep fetus
24 h after placental embolization (top) and during fetal metabolic acidosis
(bottom). Note reduction in peak IVCV, IVRV, and S⬘ during acidosis. Trace
is oriented from an apical view, such that systolic deflections are above the
zero line and toward the transducer.
studies in which the sheep fetuses maintained their cardiac
output during hypoxemia (28) and acidosis (26). Human
fetuses with clear evidence of placental insufficiency (absent or
reversed umbilical artery diastolic blood flow) are also shown
to have normal weight-indexed combined cardiac output (24).
Even fetuses with increased serum troponin-T levels seem to
have normal ventricular shortening fraction and ejection force
and appear to maintain their cardiac output (29). This explains
why signs of fetal congestive heart failure in intrauterine
growth restriction tend to occur late in the disease process and
subtle fetal cardiac dysfunction is difficult to detect using
conventional echocardiography. Therefore, TDI of fetal myocardial motion could improve the early detection of impending
heart failure.
E/E⬘ of both ventricles was increased during fetal metabolic
acidosis. In adults, mitral valve E/E⬘ has been shown to reflect
LV filling pressure (31, 33). In the present study, fetal CVP
remained unchanged, suggesting that ventricular filling pressures did not change significantly. Thus an increase in E/E⬘
was merely reflecting a depression in E⬘ wave velocity during
metabolic acidosis. E/E⬘ of the LV correlated significantly with
the severity of fetal acidosis. We propose that the fetal LV is
more sensitive to the changes in oxygenation and acid-base
status than the RV. In addition, despite the parallel arrangement of the fetal circulation, the afterload impedance faced by
the RV may be different from that faced by the LV during fetal
acidosis. In these experiments, the presence of fetal ductal
constriction was excluded by serial Doppler studies, but a
relative increase in vascular impedances, including the pulmonary vascular bed, could have occurred.
Myocardial velocities recorded by TDI during a cardiac
cycle reflect shortening and lengthening of long-axis fibers
situated predominantly in the subendocardium. In human fetuses, higher myocardial wall velocities in the RV than LV and
IVS have been attributed to segmental differences in myocardial fiber orientation (11, 32). Although there are known
MYOCARDIAL VELOCITIES IN FETAL ACIDOSIS
AJP-Heart Circ Physiol • VOL
ACKNOWLEDGMENTS
We thank Seppo Valli (GE Medical Systems) for the loan of the Vivid 7
Dimension ultrasound system and EchoPac software.
GRANTS
Financial Support for this study was obtained from the Academy of Finland.
J. C. Huhta is supported by the Daicoff-Andrews Chair in Perinatal Cardiology
of the University of South Florida and All Children’s Hospital Foundations. L.
Mertens is a Clinical Investigator for the Fund for Scientific ResearchFlanders.
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